1. Field of the Invention
The present invention relates to a composition for the prophylaxis or therapy of intraventricular hemorrhage and hydrocephalus in preterm infants, comprising mesenchymal stem cells.
2. Description of the Related Art
According to the WHO, preterm infants are babies born before completing 37 weeks gestation or before 259 days from the first day of the last menstrual period. Regardless of gestational age, low birth weight (LBW) is defined as a birth weight of a liveborn infant of less than 2,500 g, very low birth weight (VLBW) as a birth weight of a liveborn infant of less than 1,500 g, and extremely low birth weight (ELBW) as a birth weight of a liveborn infant of less than 1,000 g. Underdeveloped lungs make it difficult for preterm infants to breathe by themselves. In many cases, preterm infants further suffer from various diseases due to many other premature organs. The most representative among neurological diseases of preterm infants which leave complications for a long period of time or for their lives is intraventricular hemorrhage. Once intraventricular hemorrhage occurs, blood flows to the brain's ventricular system. Intraventricular hemorrhage in preterm infants is often described in the following four grades:
Grade 1—bleeding occurs just in the germinal matrix below and adjacent to the ventricles.
Grade 2—bleeding also occurs inside the ventricles.
Grade 3—ventricles are enlarged by the blood.
Grade 4—there is bleeding into the brain tissues around the ventricles.
Grades 1 and 2 are most common in preterm infants, and often there are no further complications because blood left after slight hemorrhage is for the most part absorbed and spontaneously healed. Grades 3 and 4 are the most serious and may result in long-term brain injury to the infant, with the accompaniment of complications including, for example, hydrocephalus (an abnormal accumulation of cerebrospinal fluid in the ventricles), convulsion, and cerebral palsy. With cerebral palsy, patients exhibit physical disability in development, chiefly in various areas of body movement, notably in the limbs, for a long period of time and often for their lives.
Intraventricular hemorrhage in preterm infants is quite different from the intracranial hemorrhage frequently observed in adults in terms of cause, bleeding locus, pathological physiology, and therapeutic modality. No certain therapy has yet been established for intraventricular hemorrhage in preterm infants, which is one of the greatest barriers to preventing or treating neonatal complications. In adults, primary spontaneous cerebral hemorrhage is, for the most part, intracerebral hemorrhage which occurs due to a spontaneous rupture of cerebral vessels. By contrast, almost all cases of cerebral hemorrhage in preterm infants are accounted by the intraventricular hemorrhage which occurs when small vessels around the germinal matrix burst and bleed into adjacent ventricles. Turning to anatomic correlations, there is a difference in the primary outbreak site of cerebral hemorrhage between adults and preterm infants. In adults, the most frequent location in terms of the occurrence of cerebral hemorrhage is at the level of the basal ganglia which are supplied by the cerebral artery bifurcations, whereas the germinal matrix, a highly vascularized, fragile region of the brain, is the most frequent location. Also, the difference of intracerebral hemorrhage between adults and preterm infants is found at mechanisms and pathophysiology. The anatomical and physiological prematurity of organs in preterm infants does not ensure constant blood pressure for the brain, so that cerebral vessels are greatly modulated in pressure. Preterm infants are also more prone to developing hyperglycemia or suffer from a rapid change in blood electrolyte level because of their decreased ability to regulate their blood sugar and electrolytes. In addition to these, other problems with physiological prematurity, such as insufficient regulatory ability in response to a body temperature change, a change in body's acidity with respiratory and metabolic conditions, etc., may induce intracerebral hemorrhage. In contrast, most causes of adult intracerebral hemorrhage are caused by tumors, traumas, and vascular diseases such as hypertension, diabetes, etc. Thus, differences between adults and preterm infants not only in the cause and type of intracerebral hemorrhage, but also in their anatomy and pathophysiology, require different therapies. In recent years, extensive studies have been done on the use of stem cells in therapy for cerebral infarction and hemorrhage. However, the application of stem cells to the therapy of intracerebral hemorrhage in preterm infants has not been previously reported, despite the high incidence.
There are reports that, of various kinds of stem cells, mesenchymal stem cells do not elicit alloreactive lymphocyte proliferative responses and that infusion or implantation of allogeneic, major-histocompatibility-mismatched mesenchymal stem cells into baboons has been well tolerated. The low immunogenic nature of mesenchymal stem cells is attributed to the fact that their cytokines and other secretions act to suppress immune responses of surrounding environments.
Given the background, the present inventors made a rational deduction that the use of mesenchymal stem cells, not autogenic, but allogeneic, in the prophylaxis and therapy of intraventricular hemorrhage and its hydrocephalus complications in preterm infants is ideal and most reasonable, and proved the deduction true in animal tests for the first time, which led to the present invention.